The protective role of NAD(P)H:quinone oxidoreductase 1 on acetaminophen-induced liver injury is associated with prevention of adenosine triphosphate depletion and improvement of mitochondrial dysfunction

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• 作者：Jung Hwan Hwang ; Yong-Hoon Kim ; Jung-Ran Noh ; Gil-Tae Gang…
• 关键词：NAD(P)H ; quinone oxidoreductase 1 ; Acetaminophen ; Acute liver injury ; Mitochondrial dysfunction
• 刊名：Archives of Toxicology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：89
• 期：11
• 页码：2159-2166
• 全文大小：1,321 KB
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• 作者单位：Jung Hwan Hwang (1)
  Yong-Hoon Kim (1)
  Jung-Ran Noh (1)
  Gil-Tae Gang (1)
  Kyoung-Shim Kim (1)
  Hyo Kyun Chung (2)
  Surendar Tadi (3)
  Yong-Hyeon Yim (3)
  Minho Shong (2)
  Chul-Ho Lee (1)
  
  1. Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 305-806, South Korea
  2. Department of Internal Medicine, Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Chungku, Daejeon, 301-721, South Korea
  3. Division of Metrology for Quality Life, Korea Research Institute of Standard and Science (KRISS), Daejeon, South Korea
  
• 刊物主题：Pharmacology/Toxicology; Occupational Medicine/Industrial Medicine; Environmental Health; Biomedicine general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-0738

文摘

An overdose of acetaminophen (APAP) causes hepatotoxicity due to its metabolite, N-acetyl-p-benzoquinone imine. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an important enzyme for detoxification, because it catabolizes endogenous/exogenous quinone to hydroquinone. Although various studies have suggested the possible involvement of NQO1 in APAP-induced hepatotoxicity, its precise role in this remains unclear. We investigated the role of NQO1 against APAP-induced hepatotoxicity using a genetically modified rodent model. NQO1 wild-type (WT) and knockout (KO) mice were treated with different doses of APAP, and we evaluated the mortality and toxicity markers for cell death caused by APAP. NQO1 KO mice showed high sensitivity to APAP-mediated hepatotoxicity (as indicated by a large necrotic region) as well as increased levels of nitrotyrosine adducts and reactive oxygen species. APAP-induced cell death in the livers and primary hepatocytes of NQO1 KO mice, which was accompanied by an extensive reduction in adenosine triphosphate (ATP) levels. In accordance with this ATP depletion, cytosolic increases in mitochondrial proteins such as apoptosis-inducing factor, second mitochondria-derived activator of caspases/DIABLO, endonuclease G, and cytochrome c, which indicate severe mitochondrial dysfunction, were observed in NQO1 KO mice but not in WT mice after APAP exposure. Severe mitochondrial depolarization was also greater in hepatocytes isolated from NQO1 KO mice. Collectively, our data suggest that NQO1 plays a critical role in protection against energy depletion caused by APAP, and NQO1 may be useful in the development of therapeutic approaches to effectively diminish the hepatotoxicity caused by an APAP overdose.